There have recently been rapid advances in molecular biology. For example, one significant accomplishment was the completion of the sequencing of the human genome. Presently, another challenge is to understand how the many protein targets encoded by the DNA interact with other proteins, small molecule pharmaceutical candidates, and a large host of enzymes and inhibitors.
To determine such interactions, assays may be completed using biosensors. Biosensors have been developed to detect a variety of biomolecular interactions including antibody-antigen, hormone-receptor, and enzyme-substrate interactions. Biosensors include a highly specific recognition element and a transducer that converts a molecular recognition event into a quantifiable signal. Signal transduction has been accomplished by many methods including fluorescence, interferometry, and gravimetry, for example.
For the majority of assays for genomics, proteomics, pharmaceutical compound screening, and clinical diagnostic applications completed using biosensors, fluorescent or calorimetric chemical labels are commonly attached to the molecules under study so these molecules may be readily visualized. However, attachment of a label substantially increases assay complexity and possibly alters functionality of the molecules through conformational modification or epitope blocking.
Detection of biomolecular interactions may be accomplished using label free detection techniques. For example, label free detection techniques include measuring changes in mass, changes in microwave transmission line characteristics, microcantilever deflection, or optical density detection.
Unfortunately, however, the widespread commercial acceptance of label free biosensor technologies has been limited by the lack of ability to provide high detection sensitivity in a format that is inexpensive to manufacture and package. For example, label free detection biosensors fabricated upon semiconductor or glass wafers are costly to produce and package if the sensor area is large enough to contain a number of parallel assays. Similarly, providing for electrical connections to individual biosensors in an array of biosensors poses difficult challenges in packaging, and compatibility with fluid exposure. In addition, many label free biosensor transduction methods (e.g., surface plasmon resonance (“SPR”), output grating coupling, ellipsometry, evanescent wave detection, and reflectance interference spectroscopy (“RIS”)) are rather slow and can be very expensive. Furthermore, some of these label free detection methods are limited to dry samples, and thus are not suited for samples immersed in fluid. This substantially limits applications for these biosensors.
As the industry evolves from the detection of genes towards identification of protein interactions for example, the emphasis shifts from simply identifying structure to identifying both structure and function. Also, there are many more proteins than genes, which increases difficulty in the identification process. Indeed, the use of labels, such as colorimetric or fluorescent tags, for genomic investigations is known to adversely affect the structure and function of some proteins. In addition, the limitations of existing label free technologies present too many obstacles to overcome. Therefore, there is a need for a new sensing mechanism that can monitor assays without the use of labels, is amenable to ultra high throughput, and can lower the cost per assay performed.